Summary of AHRQ’s Comparative Effectiveness Review of Disease-Modifying Antirheumatic Drugs for Children with Juvenile Idiopathic Arthritis

BACKGROUND: A systematic review on the comparative effectiveness of disease-modifying antirheumatic drugs (DMARDs) used to treat children with juvenile idiopathic arthritis (JIA) was published by the Agency for Health Care Research and Quality (AHRQ) in September 2011. Studies from 198 articles included in the review addressed the benefits and harms of DMARDs compared with conventional treatments and other DMARDs used to treat JIA. The review also incorporated studies comparing various clinical tools used for diagnosing JIA and measuring disease activity. Clinical outcome measures were analyzed to determine the most effective methods to measure disease state. The lack of current research for the treatment of JIA motivated AHRQ to contract with researchers to synthesize the available information with the intent of enabling health professionals to make evidence-based practice decisions for their patients. The review alsohighlights gaps in the research and areas that need to be addressed in the future. OBJECTIVES: To (a) educate health care practitioners on the findings from AHRQ’s 2011 comparative effectiveness review on DMARDs used to treat children with JIA, (b) apply review findings to make diagnosis and treatment decisions in clinical practice, and (c) recognize limitations and gaps n the current research relating to the comparative benefits and harms of DMARDs for treatment of JIA. SUMMARY: JIA is a chronic inflammatory disease affecting approximately 00,000 children and adolescents in the United States.1 Initially manifesting with inflammation, swelling, pain, and stiffness of the joints, the disease as no apparent or known cause. JIA is a clinical diagnosis based on several actors including the number of affected joints and the involvementof other tissues (e.g., the skin and lymphoid tissues), and JIA has 7 categories: systemic-onset arthritis, oligoarthritis, rheumatoid-factor positive polyarthritis, rheumatoid-factor negative polyarthritis, enthesitis-related arthritis, psoriatic arthritis, and undifferentiated arthritis. 2 Complete remission and resolution of disease activity are the ultimate treatment goals; however, there is no present cure. Inhibition of inflammation, prevention of joint damage, and promotion of a high level of functioning are the immediate goals of treatment. Even with treatment, patients with JIA continue to experience disease activity, joint destruction, suboptimal function, and impaired quality of life, all of which extend into adulthood.3 JIA can be severely debilitating and places a heavy physical and psychological burden on children and families affected by the disease. Methotrexate is a nonbiologic DMARD with an unknown mechanism of action. Methotrexate has been used for so long in the treatment of JIA that it is frequently considered a part of conventional treatment; the evidence shows that methotrexate is superior to conventional treatment with NSAIDsand/or intra-articular corticosteroids. The introduction of newer biologic DMARDs has spawned optimism that treatment will increasingly lead to improved outcomes for JIA, but the evidence is insufficient to support superiority over methotrexate. There is moderate evidence to support the claim that continued treatment from 4 months to 2 years with a biologic DMARD in children who have responded to a biologic DMARD decreases the risk of a flare. However, the safety of biologic DMARDs for long-term use has not been determined and may be associated with the developmentof cancer. The association between tumor necrosis factor (TNF) alpha inhibitors and potential increased risk of lymphoma caused the U.S. Food and Drug Administration (FDA) to place boxed warning labels on biologic DMARDs including etancercept, infliximab, and adalimumab. The effectiveness of the DMARDs appears to vary among categories of JIA and the treatment history of individual patients. Except for methotrexate, there is insufficient evidence to support selection of a specific drug or drug class over another in the treatment of JIA. The AHRQ review examines the scientific literature on DMARDs used in children with JIA in an effort to synthesize what is known about the subject, and the comprehensive review identifies important research gaps in the literature that need to be addressed. Only 8 studies (in 9 publications) were rated “good quality” by the AHRQ investigators.


Target Audiences
This CME activity is designed to meet the educational needs of physicians, pharmacists, nurses, and case managers.

Learning Objectives
Based on the findings from AHRQ' s comparative effectiveness review of disease-modifying antirheumatic drugs for children with juvenile idiopathic arthritis (JIA): 1. Compare the effectiveness of conventional treatments vs. newer synthetic or biologic disease-modifying antirheumatic drugs (DMARDs) for the following outcomes: laboratory measures of inflammation, radiographic progression, symptoms, and health status. C onventional JIA treatments-nonsteroidal anti-inflammatory drugs (NSAIDs) and systemic or intra-articular corticosteroids-may only be partially effective in reducing the severity of arthritis symptoms and in minimizing long-term complications. With recent and ongoing advances in the development of DMARDs, experts in rheumatology currently view remission as a potentially achievable goal for many children with JIA. DMARDs act by interfering with the development, activation, or function of immune cells that produce the molecular mediators of joint inflammation and damage in JIA. Nonbiologic DMARDs are manufactured chemically, whereas biologic DMARDs are produced through biologic materials and processes. 4 The nonbiologic DMARD methotrexate has been a cornerstone JIA treatment for many years. Methotrexate is thus often considered as part of a conventional treatment regimen along with NSAIDs and corticosteroids.
Given the heterogeneity of JIA (Table 1), as well as the numerous treatment options in conventional and DMARD classes (Figure 1), questions naturally arise about the comparative effects of available medications on disease symptoms, radiographic progression, function, and quality of life. Moreover, there are many concerns about the long-term safety risks of JIA medications, especially for use in children. Thus, comprehensive synthesis of published studies in this area would be of great value to clinicians who provide care for children with JIA.

■■ AHRQ's Comparative Effectiveness Review of Conventional Therapies and DMARDs for JIA
In September 2011, the Agency for Healthcare Research and Quality (AHRQ) published a comparative effectiveness review of synthetic and biologic DMARDs for JIA treatment in youths ABSTRACT BACKGROUND: A systematic review on the comparative effectiveness of disease-modifying antirheumatic drugs (DMARDs) used to treat children with juvenile idiopathic arthritis (JIA) was published by the Agency for Health Care Research and Quality (AHRQ) in September 2011. Studies from 198 articles included in the review addressed the benefits and harms of DMARDs compared with conventional treatments and other DMARDs used to treat JIA. The review also incorporated studies comparing various clinical tools used for diagnosing JIA and measuring disease activity. Clinical outcome measures were analyzed to determine the most effective methods to measure disease state. The lack of current research for the treatment of JIA motivated AHRQ to contract with researchers to synthesize the available information with the intent of enabling health professionals to make evidence-based practice decisions for their patients. The review also highlights gaps in the research and areas that need to be addressed in the future.
OBJECTIVES: To (a) educate health care practitioners on the findings from AHRQ's 2011 comparative effectiveness review on DMARDs used to treat children with JIA, (b) apply review findings to make diagnosis and treatment decisions in clinical practice, and (c) recognize limitations and gaps in the current research relating to the comparative benefits and harms of DMARDs for treatment of JIA.
SUMMARY: JIA is a chronic inflammatory disease affecting approximately 300,000 children and adolescents in the United States. 1 Initially manifesting with inflammation, swelling, pain, and stiffness of the joints, the disease has no apparent or known cause. JIA is a clinical diagnosis based on several factors including the number of affected joints and the involvement of other tissues (e.g., the skin and lymphoid tissues), and JIA has 7 categories: systemic-onset arthritis, oligoarthritis, rheumatoid-factor positive polyarthritis, rheumatoid-factor negative polyarthritis, enthesitis-related arthritis, psoriatic arthritis, and undifferentiated arthritis. 2 Complete remission and resolution of disease activity are the ultimate treatment goals; however, there is no present cure. Inhibition of inflammation, prevention of joint damage, and promotion of a high level of functioning are the immediate goals of treatment. Even with treatment, patients with JIA continue to experience disease activity, joint destruction, suboptimal function, and impaired quality of life, all of which extend into adulthood. 3 JIA can be severely debilitating and places a heavy physical and psychological burden on children and families affected by the disease.
Methotrexate is a nonbiologic DMARD with an unknown mechanism of action. Methotrexate has been used for so long in the treatment of JIA that it is frequently considered a part of conventional treatment; the evidence shows that methotrexate is superior to conventional treatment with NSAIDs and/or intra-articular corticosteroids. The introduction of newer biologic DMARDs has spawned optimism that treatment will increasingly lead to improved outcomes for JIA, but the evidence is insufficient to support superiority over methotrexate. There is moderate evidence to support the claim that continued treatment from 4 months to 2 years with a biologic DMARD in children who have responded to a biologic DMARD decreases the risk of a flare. However, the safety of biologic DMARDs for long-term use has not been determined and may be associated with the development of cancer. The association between tumor necrosis factor (TNF) alpha S4 Supplement to Journal of Managed Care Pharmacy JMCP February 2012 Vol. 18, No. 1-b www.amcp.org of current health status. Long-term outcomes included clinical remission, joint function, functional ability, pain control, quality of life, growth, development, and mortality. The conventional therapies evaluated in studies included in the AHRQ review are in 2 classes: (a) intra-articular steroids (betamethasone, triamcinolone acetonide, and triamcinolone hexacetonide), and (b) NSAIDs (celecoxib, etodolac, ibuprofen, indomethacin, meloxicam, naproxen, oxaprozin, and tolmetin). The major treatment comparisons analyzed in the included studies are illustrated in Figure 1, and the biologic and nonbiologic DMARDs (e.g., methotrexate) with status of FDA-approval for JIA are listed in Table 2.
Key Question 2: For laboratory measures, radiographic progression, symptoms, and health status, what are the comparative effects of different DMARDs? Analyzing the same outcomes as key question 1, this question focused on head-to-head comparisons of DMARDs.
Key Question 3: Do the rate and type of adverse events differ among DMARDs or between DMARDs and conventional treatments with or without methotrexate? This question primarily addressed treatment-related risks of serious infections and malignancies. In addition, adverse events of interest included nausea, vomiting, hepatitis, bone marrow suppression, mortality, and risks to the fetus or pregnant mother. aged 18 years and younger. The review was conducted by investigators at the Duke Evidence-Based Practice Center (EPC) in Durham, North Carolina. JIA was defined according to criteria established by the following 3 professional organizations: 5,6 • The International League of Associations for Rheumatology (ILAR) (  to the JIA categories summarized in Table 1, and the 8 studies (9 publications) rated "good quality" are listed in Table 3.
Key Question 5: How valid, reliable, responsive, and feasible are the various instruments used to assess clinical outcomes in practice settings and clinical trials for patients on JIA therapies? The assessment instruments that were analyzed to answer this key question are listed in Table 4. The instruments were assessed for test-retest reliability, inter-and intra-rater reliability, internal reliability, construct reliability, responsiveness (standardized response mean and responsiveness index), and feasibility metrics, including time for administration.

Summary of AHRQ's Comparative Effectiveness Review of Disease-Modifying
Antirheumatic Drugs for Children with Juvenile Idiopathic Arthritis   3 PGA is assessed by the physician asking the patient to rate pain on a visual analog scale (VAS), with a high score indicating more severe disease activity. 3 This instrument is most commonly assessed using the 100 mm VAS, with endpoints of "remission" and "very severe." Also assessed using the VAS, the PGW is administered by the parent or caretaker to determine the child's overall well-being, with anchors of "very well" and "very poorly." 4

Measuring Functional Status
The Child Health Assessment Questionnaire (CHAQ), which was adapted from the Stanford Health Assessment Questionnaire (HAQ) for adults, is the most extensively evaluated instrument for measuring functional status and disability in children. The CHAQ is designed to assess disability and discomfort, which are major indications of JIA disease activity. The instrument comprises a disability index (CHAQ-DI; 30 items, 8 domains) and 2 visual analogue scales that assess pain/discomfort and overall well-being, respectively. 4 The CHAQ-DI assesses the child's difficulty in completing various tasks. The form can be completed by the child's parents. Scores range from 0 to 3, with higher scores reflecting increased disability. The CHAQ is widely used and validated in multiple languages. The CHQ has a 28-item or 50-item form that parents can fill out and an 87-item self-administered form for children over 10 years of age. The CHQ addresses many domains including physical functioning, bodily pain or discomfort, general health, range in health, limitations in schoolwork and activities with friends, mental health, behavior, self-esteem, family cohesion, and emotional or time impact on the parent. Scores range from 0 to 100, with higher scores indicating greater well-being. 4 The PedsQL 4.0 is a self-administered questionnaire that uses brief, generic core questions to measure health-related quality of life in children aged 2 to 18 years. The Generic Core Scales include 23 items that can be facilitated to healthy school and community populations and to children with acute and chronic health conditions. 8 The scales are measured on 4 domains including physical, emotional, social, and school functioning. The PedsQL can differentiate between healthy patients and children with acute and chronic conditions, as well as indicate the morbidity and mortality burdens.

Measuring Health-Related Quality of Life
The PedsQL-RM contains 22 items that address 5 domains including pain and hurt, daily activities, treatment, worry, and dropout rates, and appropriate methods for preventing bias, measuring outcomes, and analyzing results. • Fair studies are susceptible to bias, although not to a degree that invalidates the results. Fair studies may also be characterized by missing information or methodological weaknesses. • Poor studies have significant bias that may invalidate their results. Moreover, poor studies tend to have large amounts of missing information and serious errors in design, analysis, or reporting.
In addition to assessing the methodological quality of studies included in the review, the EPC investigators evaluated the strength of study evidence, using a modified version of an instrument developed by the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) working group. 8 This evaluation considers factors regarding evidence such as directness, precision, consistency across studies, magnitude of effect, applicability, and the potential for publication bias. The evidence was graded as high, moderate, low, or insufficient. The first 3 of these grades indicate the investigators' confidence in the extent to which the evidence reflects true, or systematic, treatment effects. A grade of insufficient indicates that evidence does not either exist or permit the estimation of effects.

■■ Description of Outcome Measures
Several tools have been developed for diagnosing JIA and/or evaluating treatment outcomes in clinical trials and practice settings. Commonly used tools assess laboratory measures of inflammation, symptoms reflecting disease activity, functional status, and quality of life. The following sections describe the outcome measures that were used in studies included in the AHRQ comparative effectiveness review.

Laboratory Measures of Inflammation
Although the diagnosis of JIA is generally determined by the patient's medical history and physical exam (with or without supporting evidence of radiographic joint damage), nonspecific laboratory measures of inflammation may be used to follow disease activity and treatment response in some JIA categories. In clinical trials included in the AHRQ review, the most common laboratory measure of treatment response was the erythrocyte sedimentation rate (ESR), which is a measure of acute inflammation. 4 Another marker of inflammation is C-reactive protein (CRP), which is produced by the liver in response to tissue inflammatory processes, injury, or infection.

Assessment of Symptoms Associated with Disease Activity
Three main instruments are commonly used to assess symptoms associated with underlying JIA disease activity: active joint count (AJC), physician global assessment of disease activity (PGA), and parent/patient global assessment of well-being that lasted 48 weeks (n = 171). 11 Outcomes were stratified by whether patients in both groups were also treated with methotrexate. In comparisons of those who did not use methotrexate, the proportion of patients who experienced disease flares was lower in the adalimumab group (43%) versus the conventional treatment group (71%, P = 0.03). Among patients who also used methotrexate, the incidence of disease flares was also lower in the adalimumab group (37% vs. 65%, respectively; P = 0.02). More patients attained the ACR Pediatric 50 score in (a) the adalimumab without methotrexate group than the conventional treatment without methotrexate group (53% vs. 32%, respectively; P = 0.01) and (b) the groups that did receive methotrexate (63% for adalimumab vs. 38% for conventional treatment, P = 0.02). There was no difference in the Pediatric 90 score for adalimumab (30%) versus conventional treatment (18%, P = 0.28). Uveitis, an extra-articular manifestation of JIA, is rarely found in children with systemic JIA, but more commonly prevalent in children with polyarticular onset. A small placebocontrolled, randomized, double-masked, prospective clinical trial, which was rated as fair quality, found no apparent difference between treatment with etanercept versus placebo in 12 children with uveitis. 13 The study consisted of 2 phases, each lasting 6 months. The first phase was a double-masked randomized study, and the second phase was a single-arm, openlabel cohort study. Although this study design was not able to detect a substantial benefit for the use of etanercept in treating JIA-associated uveitis, it is possible that a treatment effect does exist and the study design failed to provide a sufficient sample size with the power to detect such a difference.
Infliximab, another TNF-alpha inhibitor, was compared with placebo in 1 double-blind RCT rated as fair quality despite inconsistent and incomplete reporting of outcomes. 13 The ACR Pediatric 50 response at 14 weeks was 50.0% (29 of 58 patients) in the infliximab group versus 33.9% (20 of 59 patients) in the placebo group (P = 0.078), and there was also no difference in the rate of clinical remission at 52 weeks for infliximab (44.1%) versus placebo (43.1%, no P value reported).
Intravenous immunoglobulin (IVIG) was compared with conventional treatment in 3 studies. 14-16 A small fair-quality discontinuation trial (n = 19) reported a 3% decrease in the AJC for IVIG-treated patients compared with a 30% increase in the placebo group. 14 The PGA score improved in 3% of the treatment group and worsened in 91% of the placebo group. In a poor-quality, open-label trial (n = 20) comparing IVIG with methylprednisolone for patients with systemic JIA, there were no significant treatment-group differences for changes in ESR over 6 months. In a poor-quality RCT with 31 patients, there were no significant differences in changes in AJC or PGA among patients treated with IVIG versus placebo (0.1% albumin). 16 Tocilizumab, a humanized antibody directed against the communication. 4 The score ranges from 0 to 100, with higher scores relating to a better quality of life. The total score is calculated from the physical score and psychosocial score, the latter of which is calculated from the average of emotional, social, and school functioning scores.

■■ Benefits of DMARDs Versus Conventional Therapies
This section addresses the AHRQ review findings relevant to key question 1 and focuses on the comparative benefits of nonbiologic or biologic DMARDs vs. conventional therapies with or without methotrexate. For each comparison, relatively few studies were identified that met the review inclusion criteria. The small number of studies included in the review, as well as their considerable differences, precluded meta-analyses for most comparisons. Thus, the findings summarized as follows are organized by individual studies and comparisons.

Benefits of Nonbiologic DMARDs Versus Conventional Treatments
Studies included in the AHRQ review compared clinical and functional outcomes for children treated with methotrexate vs. conventional medications.
A poor-quality study (n = 63) reported greater improvements in mean AJC among patients treated with methylprednisolone (-7.1) versus methotrexate (-4) or NSAIDs (-0.8, P = 0.008). 9 However, this study failed to adjust for potential confounders, and patients were not blinded to treatment assignments.
Leflunomide, an immunomodulatory agent not approved by the FDA for JIA, was compared to conventional treatment with methotrexate in only 1 RCT. This RCT (n = 94) was rated as good quality; 86 patients completed 16 weeks of treatment and 70 patients were followed in a 32-week blinded extension period. 10 There was no difference in the reduction in the mean AJC between the leflunomide and methotrexate groups (-8.1 vs. -8.9, respectively; P value reported as "not significant"). There were also similar magnitudes of improvement in the leflunomide and methotrexate groups for CHAQ scores, PGA, PGW, and ESR. There were trends toward higher rates of ACR Pediatric 30, 50, and 70 responses for patients treated with methotrexate. For example, between weeks 16 and 48, 70% of patients in the leflunomide group achieved an ACR Pediatric 70 response versus 83% in the methotrexate group. However, there was no improvement between week 16 and week 48 for either the leflunomide (P = 0.10) or methotrexate (P = 0.06) groups, and no between-group statistical comparison was made.

Benefits of Biologic DMARDs Versus Conventional Treatments
Adalimumab, a fully human anti-tumor necrosis factor (TNF) alpha monoclonal antibody, was compared with conventional therapy in 1 good-quality randomized discontinuation trial

Summary of AHRQ's Comparative Effectiveness Review of Disease-Modifying
Antirheumatic Drugs for Children with Juvenile Idiopathic Arthritis methods were flawed by drug switching, lack of blinding to therapy, and withdrawals due to noncompliance and adverse events. Among the 10 children in the etanercept arm, 1 was withdrawn for noncompliance. Among the 14 children receiving infliximab, 4 withdrew due to adverse events and 1 withdrew because of lack of efficacy (failure to attain ACR Pediatric 50 criteria). After 12 months of treatment, there was no difference in the mean decrease in AJCs for etanercept (-9.5, 95% CI = -19 to -3) versus infliximab (-11.5, 95% CI = -17 to -7.

■■ Comparative Risks of DMARDs and Conventional Therapies
This section addresses key question 3, which focuses on types and rates of adverse events in comparisons between different DMARDs or between DMARDs and conventional treatments. Unfortunately, few head-to-head DMARD trials have been conducted on children with JIA; thus, the evidence is weak for the comparative risks of specific drugs or drug classes. The EPC investigators identified 13 placebo-controlled RCTs that reported adverse events associated with JIA therapies. Rates of adverse events were generally similar across the published RCTs. The review identified 11 incident cases of cancer among several thousand children treated with 1 or more DMARDs. 4 An additional 2 publications identified 66 cases of malignancies diagnosed in children undergoing treatment that included TNF-alpha inhibitors. [23][24] The EPC investigators recommend interpreting these data with caution, because the adverse events were not systematically collected or reported across the studies. In addition, because some clinical trials excluded patients who did not tolerate an intervention during a drug run-in phase, adverse event rates may be underestimated.
Methotrexate was compared with placebo in a double-blind RCT that lasted 6 months. 19 Among the 86 patients in the methotrexate group, 3% dropped out due to adverse events, 12% reported a gastrointestinal event, 7% reported pain, and 35% had a laboratory abnormality. No patients dropped out due to adverse events in the placebo arm. Sulfasalazine was compared with placebo in a good-quality, 6-month RCT. 25 Of the 35 patients in the sulfasalazine arm, 29% dropped out due to adverse events. Reported events included gastrointestinal (29%), dermatologic (26%), neurologic (26%), and hematologic (6%) abnormalities. In addition, 6% of patients treated with sulfasalazine had elevated liver enzymes, and 4% had other laboratory abnormalities. All of the reported rates of adverse events were higher for the sulfasalazine group than the placebo group. IL-6 receptor, was compared with conventional treatment for patients with systemic JIA in a fair quality randomized discontinuation trial (n = 43) of 56 patients who completed the openlabel lead-in phase and achieved an ACR Pediatric 30 response and CRP concentration > 5 mg per dL. 17 There were no P values reported in this study for the outcomes. In the RCT component of this study, the AJC decreased in both the tocilizumab group (from 3.5 to 0) and the conventional treatment group (from 4 to 0). Improvements in CHAQ scores were reported for both groups (-0.5 vs. -0.25, respectively). Both the PGA and PGW also improved, and the ESR decreased for both groups. The percentage of patients achieving ACR Pediatric 70 criteria increased in the tocilizumab group (from "approximately 70% to approximately 80%") and decreased in the conventional treatment group (from "approximately 80% to approximately 30%").

■■ Comparative Benefits of Nonbiologic DMARDs or Biologic DMARDs
This section, which addresses the findings relevant to key question 2, focuses on clinical and functional outcomes reported in studies that compared different nonbiologic DMARDs or different biologic DMARDs. Very few studies were identified that directly compared the effects of DMARDs in children with JIA. Moreover, the evidence was generally insufficient to determine whether any specific drug or drug class is associated with better outcomes. No studies included in the AHRQ review compared a nonbiological DMARD with biologic DMARD. age 53 months, she died of Legionella pneumonia. Her autopsy revealed previously undiagnosed stage IV lymphoma. Studies included in the AHRQ review reported 10 cases of cancer, including 7 lymphomas. For studies comparing etanercept plus methotrexate with etanercept alone, there were 2 cases of thyroid carcinoma, 29-30 1 case of yolk sac carcinoma, 30 and 2 cases of lymphoma. [30][31] Among patients who had been treated with infliximab, etanercept, and methotrexate, 2 cases of lymphoma were reported. 31 Three cases of lymphoma were reported in studies in which patients were treated with methotrexate alone. [32][33][34] Aside from these cases of cancer reported among the several thousand patients who participated in the studies included in the AHRQ review, there was no clear evidence of a high incidence or prevalence of any serious adverse event associated with DMARDs.
In a search of the U.S. FDA Adverse Event Reporting System through April 2008, Diak et al. identified 48 cases of malignancies in people 22 years or younger who were treated with the TNF-alpha inhibitors infliximab, etanercept, or adalimumab. 23 Half of these cases were lymphomas, with the majority (88%) involving the concomitant use of other immunosuppressants. From a search of clinical trials and global safety databases, McCroskery et al. identified 15 confirmed and 3 potential malignancies in children with JIA who were treated with etancercept. 24 The confirmed cases included 7 lymphomas. The size of the population from which these cases were identified was not reported; thus, the researchers were not able to accurately estimate event rates or compare them to the baseline event rates for the population not exposed to TNF-alpha inhibitors.

■■ Effectiveness and Safety of DMARDs for Various Categories of JIA
The Duke EPC investigators devised key question 4 in order to assess the comparative effectiveness of different DMARDs for children with various categories of JIA (Table 2). 2 IL-1 inhibitors, including anakinra, rilonacept, and canakinumab, are mainly used for treating systemic JIA, while IL-6 inhibitors such as tocilizumab are more effective at treating systemic JIA and can be used to treat polyarticular JIA. The investigators reasoned that treatment outcomes may vary for patients with different disease types, stages, and severity. However, a thorough search of the literature revealed that the existing evidence is "insufficient" to evaluate the efficacy, effectiveness, or adverse events associated with DMARDs for children in different JIA categories. The lack of evidence is primarily attributable to the small numbers of subjects enrolled in existing studies and the complex nature of stratifying patients by disease category. The EPC investigators identified only 1 study to answer question 4 regarding the comparative effectiveness of the DMARDs in children in the different JIA categories. Woo et al. (2000) assessed the efficacy of methotrexate in 43 children with extended oligoarticular JIA and 45 children In a good-quality randomized study (n = 62) comparing abatacept with placebo, no adverse events were reported for either group. 26 For anakinra, a 16-week study judged to be fair quality which changed from a study of efficacy to one reporting safety outcomes, found that 6 of 25 patients (24%) who received anakinra had gastrointestinal events, 8% had dermatologic events, 12% had fever, 6% reported pain, and 28% had other adverse events in the anakinra arm. None of the adverse events were considered serious, and these rates were reported as "similar" for the placebo group except for 10 patients (40%) who reported dermatologic events compared with 2 patients in the anakinra group.
Etanercept was compared with placebo in 1 goodquality study of children with polyarticular JIA (n = 25). 27 Gastrointestinal events were reported in 4% of patients in the treatment arm, and there were no dropouts due to adverse events. Another fair-quality study that evaluated the safety of etanercept for the treatment of uveitis reported unspecified infection in 5 of 7 patients (71%) who received etanercept versus 3 of 5 patients (60%) who received placebo. 12 Infliximab plus methotrexate was compared with placebo plus methotrexate in a fair-quality multicenter, international RCT with an open-label extension. 13 The study reported outcomes inconsistently, the nature of the serious adverse events was not specified, and reporting of adverse events was insufficient for comparison of infliximab versus placebo. Infections were reported in 68.3% of 60 patients who received infliximab 3 mg per kg plus methotrexate over 52 weeks versus 64.9% of 57 patients who received 6 mg per kg infliximab plus methotrexate and 46.7% of 60 patient show received placebo plus methotrexate. Serious adverse events were reported in 5.0% of patients in the placebo group over 14 weeks and in 32% of patients in the infliximab group over 52 weeks. The 3 mg per kg dose was associated with a higher rate of serious adverse events, infusion reactions, and the formation of antibodies compared with the 6 mg per kg dose. Lower doses of infliximab have a less favorable safety profile, which sets a basis for using higher dosing rates in children compared with adults. Due to the chimeric nature of infliximab, a higher risk for infusion reactions and allergies has been found compared with other TNF-alpha inhibitors.
Tocilizumab was compared with placebo in a fair-quality 12-week double-blind RCT phase preceded by a 6-week runin phase. 17 There was a 5% dropout rate in each arm due to adverse events. Among the 20 patients in the tocilizumab group, 5% reported a gastrointestinal event, 10% reported a respiratory event, and 5% reported a mononucleosis infection.
Other events associated with DMARD therapy, which were infrequently reported, included asthenia, malaise, hostility, and taste disturbance. DMARD use may have been associated with 1 death, which was reported in a girl on immunosuppressive therapy with cyclosporine A and methotrexate. 28

Measuring Responsiveness
Responsiveness is defined by reproducibility and the ability to register relevant changes in scores when a patient's symptom status demonstrates improvements or deterioration. No universally recommended measure of responsiveness currently exists, and most rely on calculations of effect size, which is a unitless standardized measure of changes in assessment scores. The standardized response mean 44 and the responsiveness index 45,46 produce useful information for measuring response variance. Both of these statistics can be used to calculate effect size. Receiver operating characteristic (ROC) curves can be used to measure how well various changes in scale scores distinguish improved and unimproved patients. Effects sizes of 0.2 to 0.3 are considered small, 0.5 is a medium effect, and 0.8 is a relatively large effect. 47 In analyses of 6 studies 48-53 on the responsiveness of the CHAQ, effect sizes ranged from 0 to 0.5. The CHAQ was less responsive for patients with oligoarticular disease compared with polyarticular disease. [48][49][50][51][52] PGA was the most responsive of the global assessment measures and joint count indices. [50][51][52] Moderate to high responsiveness was also found for AJC and swollen joint count. 51

■■ Directions for Future Research
As recognized by the Duke EPC investigators, many issues regarding the treatment of JIA remain unresolved. The limiting factors are often related to gaps and methodological limitations in the existing research. Thus, in concluding their comparative effectiveness review, the investigators call for future research that directly addresses the current shortcomings. Their suggestions include novel studies designed to provide data on longterm benefits and harms of JIA therapies. For valid outcomes, this line of research depends on the refinement of instruments that comprehensively, accurately, and reliably assess ongoing treatment responses. Another critical issue for future research involves the heterogeneity of JIA, given its different definitions and disease categories. Thus, new studies should be designed to determine whether the effects of given therapies differ across disease subtypes. Of course, major challenges for such clinical trials include recruiting sufficient numbers of patients affected by the different categories of JIA and following patients over suf-with systemic JIA. 35 When the 2 JIA categories were analyzed separately, there were no significant differences in clinical outcomes, but Woo et al. did find significant clinical improvement with methotrexate treatment over this 12-month study when patients in the 2 JIA categories were combined. Safety data and adverse events were not reported by Woo et al. The Duke EPC investigators concluded that they could "not identify any studies that provide reliable information on the comparative safety or rates or types of adverse events among the various categories of JIA."

■■ Assessment of JIA Outcomes Instruments
For key question 5, the Duke EPC investigators assessed the validity, reliability, responsiveness, and feasibility of the instruments used to measure outcomes of JIA treatments in clinical trials or practice settings. The investigators identified 34 studies (n = 14,381) that reported reliability, validity, and/or responsiveness of selected outcomes measures. Major findings from these psychometric evaluations are summarized in the following sections.

Measuring Reliability
Reliability measures the consistency of the instrument for assessing the outcome of interest. The EPC investigators evaluated 3 areas of reliability: reproducibility, inter-rater reliability, and internal consistency. Reproducibility, or test-retest reliability, measures the instrument's ability to produce the same measurement repeatedly without changes in the patient's status. A key finding, demonstrated in 5 studies, indicated that the CHAQ had high test-retest reliability, with correlations between 0.79 and 0.96. [36][37][38][39][40] Moreover, strong correlations for inter-rater reliability were also observed for measures of functional status or disability on the CHAQ, CHQ physical score, PedsQL, and the PedsQL-RM.

Measuring Validity
Validity reflects how well an instrument measures what it is actually intended to measure. For some clinical outcomes measures, there is no reference standard for validity. However, for others such as joint inflammation, synovial biopsy is the reference standard. Therefore, validity was assessed according to the degree by which the measures correlated with other indicators of disease, including global assessments, articular counts, and scores from other validated instruments. The AHRQ review focused specifically on the validation of the instruments for children with JIA. The CHAQ correlated less well with AJC for children early in the course of disease than for children later in the course of disease (0.14 and 0.61, respectively). For children in the later stages of the disease, the CHAQ had a strong correlation with limited range of motion (0.76), but had lower correlations with the PGA (0.51). 41

Conclusions
The AHRQ review on DMARDs used to treat children with JIA found, with a moderate strength of evidence, that biologic DMARDs decreased the risk of flares in randomized discontinuation trials for children who had responded to a biologic DMARD. Among the nonbiologic DMARDs, methotrexate was found superior to conventional therapy based on 2 RCTs with 215 patients. There were insufficient data to evaluate the effect of DMARDs on radiologic progression.
A low strength of evidence shows inconsistent improvement in health status associated with treatment of JIA with DMARDs. Direct comparisons of nonbiologic DMARDs (penicillamine, hydroxychloroquine, sulfasalazine, leflunomide, and methotrexate) demonstrated similar efficacy for health status; however the precision of measurements of changes in health status between treatment arms was insufficient to detect a difference. One poor quality RCT found etanercept to be similar to infliximab in health status. Low strength of evidence from 4 RCTs and 1 cohort study shows that ESR as a laboratory measure of inflammation is inconsistently associated with response to treatment with DMARDs.
The evidence was rated insufficient to determine if either the rates and types of adverse events differ among the various DMARDs or if there is a difference in these outcomes in treatment across the various categories of JIA. The totality of evidence available from only 3 RCTs shows that the rate and types of adverse events did not differ between DMARDs (i.e., penicillamine vs. hydroxychloroquine and leflunomide vs. methotrexate), but valid comparisons were not possible because of high variability in the determination and reporting of adverse events across the studies. There were no RCTs that compared a DMARD to conventional treatment, and the 13 trials for comparison of a DMARD to placebo showed the rate of adverse events to be similar for DMARDs and placebo except 1 study that reported 32% of patients experienced adverse events for the combination of infliximab with methotrexate versus 5% for placebo and a 35% rate of laboratory abnormalities with the combination versus 13% for placebo. Data derived from adverse event reporting databases suggest that cancer, particularly lymphoma, may be related to exposure to TNF-alpha inhibitors. For the question of safety and rate of adverse events for the DMARDs among the various JIA categories, no studies were found that provided reliable evidence; in the only RCT that addressed the question, methotrexate was similar to placebo in 2 JIA categories (extended oligoarticular and systemic).
The strength of the evidence was also found to be insufficient to answer the question regarding validity, reliability, responsiveness, and feasibility of the clinical outcome measures for childhood JIA used in clinical practice and clinical trials. No instrument or outcome measure was found superior to another in measuring disease activity, functional status, or responsiveness to changes in disease state. The ACR Pediatric ficiently long time periods to account for characteristic fluctuations in disease activity and to measure long-term outcomes.
With regard to reaching conclusions through systematic reviews of the existing literature, a considerable drawback is the lack of consistency in study outcome measures. For example, among the studies included in the AHRQ review, there was notable variation in laboratory measures of inflammation as well as inconsistent assessment of AJCs, incidence of flares, and quality of life. The EPC investigators also propose new studies to: • Determine the comparative effectiveness of specific DMARDs that are characterized by unique mechanisms of action (e.g., TNF-alpha inhibitors vs. IL-6 receptor antagonists) • Compare the benefits and risks of DMARDs for patients at various points along the disease spectrum (e.g., at presentation, after failing conventional treatment) • Identify the comparative effects of DMARDs on specific health conditions associated with JIA, including uveitis and macrophage activation syndrome • Assess the incidence of treatment-related adverse events over long periods, through prospective cohort designs In addition to these ideas for future studies, the EPC investigators suggest the establishment of JIA registries that collect outcomes data for patients treated with conventional therapies and DMARDs.
Current research on JIA is unfortunately insufficient to determine the rates and types of adverse events that can occur in patients treated with DMARDs and conventional therapies. The effects of JIA place a tremendous burden on the patient, family, and society as a whole. Ongoing research to determine the most effective outcome measures, laboratory biomarkers, and treatment interventions for JIA will guide physicians and other health care providers in making informed clinical decisions.
While the current research is a valid starting point for identifying the most effective and safe treatment options for children with JIA, other factors must be considered when making treatment decisions for individual patients. These considerations include, but are not limited to JIA category, disease severity, disease duration, prognostic factors, age, drug toxicities, drug safety monitoring, use of physical and/or occupational therapy, previous drug failures, multi-drug regimens, route of drug administration, access to medications, etc. A recommended treatment algorithm that attempts to account for many of these considerations was recently proposed by the ACR. 54 However, with such complexities in therapeutic decision making, the care of children with JIA is best done directly by, or with guidance from, a health care provider with experience and/or training in caring for patients with JIA, such as a pediatric rheumatologist.

Summary of AHRQ's Comparative Effectiveness Review of Disease-Modifying
Antirheumatic Drugs for Children with Juvenile Idiopathic Arthritis S14 Supplement to Journal of Managed Care Pharmacy JMCP February 2012 Vol. 18, No. 1-b www.amcp.org strength of evidence of efficacy. Although the available evidence suggests that the risk of harm associated with methotrexate is similar to placebo, 1 study reported more adverse events compared with placebo for methotrexate used in combination with infliximab. Evidence of efficacy from randomized discontinuation for the biologic DMARDs is offset by the unknown safety of these drugs in children, particularly in long-term use. There is insufficient evidence of efficacy to support the use of one DMARD over another.
30 is a combined measure that includes articular indices, functional status, laboratory measures, and global assessments, and accounts for the various measures most commonly used to assess JIA disease activity. However, the ACR Pediatric 30 is a relative measure of disease activity and not a measure of current disease state. The ratio of benefit versus harm in the treatment of JIA with DMARDs cannot be determined from the available evidence. Methotrexate is the most studied DMARD and has a moderate Summary of AHRQ's Comparative Effectiveness Review of Disease-Modifying Antirheumatic Drugs for Children with Juvenile Idiopathic Arthritis Juvenile idiopathic arthritis (JIA) affects 300,000 children in the United States. 1 However, the direct cost of JIA in 1992 was estimated at $285 million with a mean annual direct cost of $7,905 per child. 55 With the introduction of high-cost treatments, such as the biologic disease-modifying antirheumatic drugs (DMARDs), the costs of managing JIA have likely increased significantly in the last 30 years. Children with arthritic conditions are also seen by physician offices and emergency rooms numerous times per year. 56 Additionally, most children with JIA will continue to have symptoms and disease activity into adulthood. 57,58 Although patients with JIA represent a relatively small portion of the population, these are high-cost, high-utilizing patients who will have increased costs from childhood well into adulthood. Therefore, managed care organizations can play an important role in providing optimal clinical care, controlling costs, and ensuring appropriate use of the medications used to treat JIA. This AHRQ systematic review examined studies comparing the efficacy and safety of nonbiologic DMARDs, biologic DMARDs, and conventional therapies in the treatment of JIA. However, the authors of the review recognize the paucity of data in this area. The authors considered there to be insufficient evidence regarding the comparison of efficacy between biologic and nonbiologic DMARDs to conventional therapy and were unable to provide a meta-analysis of the results. Instead the results of individual studies are reported. Additionally, the authors also found insufficient evidence regarding the comparison of efficacy between DMARDs to determine if any drug class was associated with better outcomes. The safety of DMARDs and conventional therapies was also reported, but due to inconsistent methodologies among studies, the authors recommended interpreting the results with caution and thus reported the results for individual studies.
Unfortunately due to limitations in the current literature, this systematic review is unable to provide direction to managed care organizations with regard to the comparative effectiveness of drug classes to aid in formulary and coverage decisions. However, the review does provide an important starting point for these decisions by synthesizing the results of many individual studies into a single report and grading the evidence found. This review also underscores the need for decision makers to carefully evaluate the literature before making coverage decisions, especially when little evidence is available. Finally, this review highlights the need for high-quality comparative effectiveness research for JIA treatments, especially with regard to long-term outcomes.